MAJOR ARTICLE
HIV/AIDS
Mortality and Treatment Outcomes of China’s
National Pediatric Antiretroviral Therapy
Program
Yan Zhao,1 Chunming Li,1 Xin Sun,1 Weiwei Mu,1 Jennifer M. McGoogan,1 Yun He,2 Yuewu Cheng,3 Zhirong Tang,4
Huiqin Li,5 Mingjian Ni,6 Ye Ma,1 Ray Y. Chen,7 Zhongfu Liu,1,a and Fujie Zhang1,8,a
1
National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 2Provincial Infectious Disease
Hospital, Henan, 3Shang Cai Country Center for Disease Control and Prevention, Henan, 4Regional Center for Disease Control and Prevention, Guangxi
Zhuang Autonomous Region, 5Provincial Center for AIDS Care, Yunnan, and 6Regional Center for Disease Control and Prevention, Xinjiang Uighur
Autonomous Region, China; 7Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
and 8Beijing Ditan Hospital, Capital Medical University, China
(See the Editorial Commentary by Sugandhi and Harwell on pages 745–6.)
Background. The aim of this study was to describe 3-year mortality rates, associated risk factors, and longterm clinical outcomes of children enrolled in China’s national free pediatric antiretroviral therapy (ART) program.
Methods. Records were abstracted from the national human immunodeficiency virus (HIV)/AIDS case reporting and national pediatric ART databases for all HIV-positive children ≤15 years old who initiated ART prior to
December 2010. Mortality risk factors over 3 years of follow-up were examined using Cox proportional hazards
regression models. Life tables were used to determine survival rate over time. Longitudinal plots of CD4+ T-cell
percentage (CD4%), hemoglobin level, weight-for-age z (WAZ) score, and height-for-age z (HAZ) score were
created using generalized estimating equation models.
Results. Among the 1818 children included in our cohort, 93 deaths were recorded in 4022 child-years (CY) of
observed time for an overall mortality rate of 2.31 per 100 CY (95% confidence interval [CI], 1.75–2.78). The strongest
factor associated with mortality was baseline WAZ score <−2 (adjusted hazard ratio [HR] = 9.1; 95% CI, 2.5–33.2),
followed by World Health Organization stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1–5.2), and hemoglobin
<90 g/L (adjusted HR = 2.2; 95% CI, 1.2–3.9). CD4%, hemoglobin level, WAZ score, and HAZ score increased over time.
Conclusions. Our finding that 94% of children engaged in this program are still alive and of improved health after 3
years of treatment demonstrates that China’s national pediatric ART program is effective. This program needs to be
expanded to better meet treatment demands, and efforts to identify HIV-positive children earlier must be prioritized.
Keywords.
HIV; mortality; pediatric; antiretroviral therapy; China.
As of 2010, an estimated 3.4 million children >15 years
old were human immunodeficiency virus (HIV)–
positive worldwide. Although the number of children
receiving antiretroviral therapy (ART) increased to
Received and accepted 4 September 2012; electronically published 21 November 2012.
a
Z. L. and F. Z. contributed equally to this work.
Correspondence: Fujie Zhang, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Xi
Cheng District, Beijing 100050, PR China ([email protected]).
Clinical Infectious Diseases 2013;56(5):735–44
© The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cis941
456 000 in 2010, there is still a substantial gap in ART
coverage for children globally [1]. Since the introduction of ART, pediatric HIV mortality in developed
countries has fallen below 1 per 100 child-years (CY),
with the majority of children now reaching adolescence
and adulthood [2, 3]. In the past several years, many
resource-limited countries have published outcomes of
large-scale pediatric cohorts, with mortality rates of
children on ART ranging from 2.2 to 11.6 per 100 CY
in Africa [4–9], 1.9 to 5.2 per 100 CY in Asia [10–13],
and 0.8 per 100 CY in South America [14], Typically,
the majority of deaths among HIV-positive children on
ART occur within the first 6 months of treatment [6].
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Mortality risk factors include low baseline CD4+ T-cell percentage (CD4%), low weight-for-age z (WAZ) score, and
World Health Organization (WHO) stage III or IV disease at
treatment initiation [3, 5, 10, 15].
As of the end of 2011, the estimated number of people living
with HIV/AIDS in China was 780 000, 1.1% of whom were infected through mother-to-child transmission [16]. More than
150 000 HIV-positive patients have thus far received treatment
via China’s national free antiretroviral treatment program [16].
As a result of this program, HIV-positive adults receiving ART
now experience a dramatically reduced HIV-related mortality
rate of approximately 5 deaths per 100 person-years [17, 18].
Due to the unavailability of pediatric ART formulations in the
early years of China’s national ART program, a small portion
of HIV-positive children were treated using adult formulations
by splitting pills. In 2005, the national pediatric ART program
was launched in the 6 Chinese provinces with the highest HIV
prevalence (Henan, Anhui, Hubei, Yunnan, Shanxi, and
Guangxi) [19]. By 2010, the pediatric ART program had expanded to 28 provinces and autonomous regions [16].
Early in the pediatric ART program, treatment guidelines
were developed and extensive clinical training was provided to
local healthcare workers. Recommended first-line treatment
regimen was zidovudine (AZT) or stavudine (D4T) plus lamivudine (3TC) plus nevirapine (NVP) or efavirenz (EFV).
NVP was preferred for children <3 years or <10 kg. Free
CD4+ T-cell count and CD4% testing was provided every 6
months for all pediatric ART patients and follow-up visits
were conducted for all patients every 3 months. In 2008, ART
eligibility criteria were expanded to include all children with
(1) WHO stage III or IV disease, or (2) CD4+ T-cell counts
<350 cells/µL or CD4% <15% for children >3 years old, CD4+
T-cell counts <750 cells/µL or CD4% <20% for children 1–3
years old, or virologically diagnosed children <1 year old regardless of CD4+ cell count or CD4%. Also starting in 2008,
free annual plasma viral load ( pVL) testing was provided to
all pediatric ART patients [19].
Although 2 reports examining small cohorts of children in
China’s pediatric ART program have been published in the
past 5 years [20, 21], no nationwide cohort study exists thus
far describing outcomes for children on ART in China. It is in
this context that we present the following descriptive study,
aiming to examine mortality, its predictors, and treatment
outcomes among HIV-positive children in China’s national
pediatric ART program over 3 years of follow-up.
METHODS
Study Design
This study was designed to be a nationwide, retrospective
cohort study of HIV-positive children in China enrolled in
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China’s national pediatric ART program from 1 July 2005 to
31 December 2010.
Sources of Data
All cases of HIV in China are reported via the national HIV/
AIDS case reporting system. Records in this system include
identification and demographic information, HIV testing
results, self-reported transmission route, and health status information. When these patients initiate ART, their treatment information is reported in either the pediatric ART system (all
children <15 years old at time of ART initiation) or adult ART
system (all individuals ≥15 years old when ART was initiated
and children <15 years old who either initiated ART prior to
2005, were entered into the adult system mistakenly, or were
treated at a clinic that did not have a pediatric ART program).
In general, these systems retain information related to the clinical management of the patient and all ART-related information
(ie, drugs and doses, CD4 and pVL test results) as well as standard identification and demographic information [22].
However, some of the information in the adult and pediatric
ART databases is dissimilar. For example, CD4%, growth indicators and HIV testing method (HIV infection is determined
by enzyme-linked immunosorbent assay and Western blot if
the child is ≥18 months old or by DNA/RNA if the child is
<18 months old), are only included in the pediatric ART
system. Also, some patients in the pediatric ART system do not
have true baseline (prior to ART initiation) data because they
initiated ART before the pediatric ART program started and
were only later followed in this system. Data were censored on
31 December 2010, and national HIV/AIDS case reporting
system and pediatric ART system datasets were linked by identification number, treatment number, and name.
Study Participants
Inclusion criteria for this study were (1) having an HIVpositive serostatus, (2) being ≤15 years old when first identified as HIV positive, and (3) having a record in China’s national HIV/AIDS case reporting system as of 31 December
2010. Patients were then excluded if any 1 of the following
criteria applied: the patient (1) died before initiating ART, (2)
was not being followed in the pediatric ART system but was
instead being followed in the adult ART system, (3) had been
lost to follow-up prior to initiating ART, (4) had not yet initiated ART as of 31 December 2010, or (5) had initiated ART
before the pediatric ART system was created.
Active patients were defined as those with a follow-up
record within 3 months of 31 December 2010. Data were stratified using 3 age groups at the time of ART initiation: ≤35
months, 36–59 months, and ≥60 months—for comparison
of demographic and clinical characteristics and for analysis of
mortality and factors associated with death. Further analysis of
mortality rates, survival rates, and outcomes focused on the
first 36 months after ART initiation.
Observed Time and Treatment Outcomes
Observed time was calculated in CY from ART initiation date until
study end date or death, whichever occurred first. Immunological success was defined as CD4% ≥25% [23]. Weight-for-age z
(WAZ) score and height-for-age z (HAZ) score was calculated
according to the China National Growth Standards [24]. Viral
suppression was defined as pVL <400 copies/mL. Because free
pVL testing was not available until after 2008, only a subset of
study participants had pVL test results in their records.
Statistical Analysis
Baseline characteristics were described using median and interquartile range (IQR) for continuous variables and number and
percentage for categorical variables. Mortality rate was calculated by dividing the total number of subjects who died within
each 6-month interval by the sum of observed time for subjects
within the same interval. Life tables were used to determine
survival over time with risk factors for mortality analyzed using
Cox proportional hazards regression models. Univariate factors
with P < .1 and factors predetermined to be clinically meaningful were included in the full multivariable regression models.
Missing data were given no special treatment and multivariate
regression analysis was performed only on complete cases. All
P values are 2-sided, and P < .05 was considered to be statistically significant. Longitudinal plots of CD4%, hemoglobin,
WAZ score, and HAZ score were created using median values
every 6 months, with generalized estimating equation models
used to compare clinical outcomes at different time intervals
after ART initiation. All statistical analyses were performed
using SAS software (version 9.1.3, SAS Institute).
Ethical Approval
This study was reviewed and approved by the Institutional
Review Board of the National Center for AIDS/STD Control
and Prevention, Chinese Center for Disease Control and Prevention (CDC). Parents or legal guardians signed informed
consent forms before their children initiated ART. Because
data used in this study were collected as a function of China’s
routine HIV/AIDS surveillance program and the regular administration of the national pediatric ART program, no additional informed consent for inclusion of these data in the
study was required.
RESULTS
Characteristics of the Study Population
The development of our study cohort is described in Figure 1.
As of 31 December 2010, a total of 6085 HIV-positive children
≤15 years old when they were first identified as HIV-positive
had records in the national HIV/AIDS case reporting system,
thus making them eligible for the study. However, after applying exclusion criteria, the final cohort was 1818 children, all of
whom were included in our analysis. Among these 1818 children, 89.4% were alive and active in the pediatric ART
program, 2.7% had no follow-up record for >3 months, 2.8%
had withdrawn from the program, and 5.1% had died while
receiving treatment via the pediatric ART program.
As shown in Table 1, the median age of participants was
74.5 months (IQR, 46.5–119.6) with 63.3% of children ≥60
months old when they initiated ART. Most children were
male (57.4%), had acquired HIV via mother-to-child transmission (90.9%), and presented for treatment at WHO stage
III or IV (57.4%). Median WAZ score was −1.4 (IQR, −2.1 to
−0.8), median HAZ score was −2.2 (IQR, −3.3 to −1.1),
median CD4% was 8.8% (IQR, 3.3–14.9), and median hemoglobin level was 111.0 g/L (IQR, 99.0–122.0). The proportion
of children who presented in WHO stage III or IV disease, the
median WAZ and HAZ scores, and hemoglobin levels were
very similar across the 3 age categories, whereas median
CD4% declined with increasing baseline age category.
Observed Time, Mortality Rate, and Predictors of Death
Median observed time was 24.4 months (IQR, 10.0–40.9, data
not shown). As shown in Table 2, a total of 93 deaths were observed in 4022 CY of observed time, for an overall mortality rate
of 2.31 per 100 CY (95% confidence interval [CI], 1.75–2.78).
Patients with hemoglobin levels <90 g/L had the highest mortality rate at 6.07 per 100 CY. Results from multivariate analysis
identified having a baseline WAZ score <−2 as the strongest
factor associated with death (adjusted hazard ratio [HR] = 9.1;
95% CI, 2.5–33.2), followed by WHO stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1–5.2), and hemoglobin <90 g/L (adjusted HR = 2.2; 95% CI, 1.2–3.9). No other factors were found
to have statistically significantly associations with mortality.
As shown in Figure 2, upon closer examination of the first
36 months after treatment initiation, we found that overall
mortality declined from 7.5 per 100 CY during the initial 6
months of treatment to 1.9 per 100 CY from 6 to 12 months,
and then remained approximately 1.0 per 100 CY from 12 to
36 months. More than 94% of patients on treatment were still
alive at 3 years.
Clinical Treatment Outcomes
As shown in Figure 3, the proportions of children who
achieved immunologic success (CD4% ≥25%) increased over
the entire 3-year follow-up period, but most dramatically
during the first year after ART initiation for all age groups.
CD4% recovery in children ≤35 months of age at ART initiation was more rapid than in the 2 other age groups. Following
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Figure 1. Flowchart showing patients included in the analysis. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus.
treatment initiation, CD4%, hemoglobin level, WAZ score,
and HAZ score all increased significantly over time for all 3
age groups compared to baseline (P < .01). The one exception
was HAZ scores for children ≥60 months old at time of ART
initiation. The proportions of children who achieved virological success ( pVL < 400 copies/mL) are presented in Figure 4.
A total of 1149 of 1818 children (63%) received HIV pVL
testing in 2010. Among these children, approximately 82%
(940 of 1149) had achieved viral suppression, most of whom
had already been on ART for ≥24 months.
DISCUSSION
The aim of this study was to describe mortality, survival, risk
factors, and treatment outcomes among a nationwide cohort
over 3 years of follow-up. Our main finding is that mortality
rates for this cohort are 2.31 per 100 CY with 94% of children
surviving after 3 years of ART. Effective ART is well known to
reduce HIV morbidity and mortality among children [25],
with immunologic and virologic responses comparable in both
well-resourced and resource-limited settings [26, 27], We find
that mortality is greatest within the first 6 months of treatment
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(7.5 per 100 CY), but that by 12 months it has stabilized to a
new level (approximately 1.0 per 100 CY). This pattern has
been observed in previous studies [6, 10, 13, 27–29], though
the new stabilized mortality rate varies (<1 per 100 CY in developed countries [3, 30] and 3 to 8 per 100 CY in developing
countries [9, 30]). The findings presented here represent the
first from such a cohort in China, with only 2 smaller studies
having been performed within the context of this program
previously—one that examined treatment outcomes among
only 83 children in 2005 [20], and the other that examined
drug resistance among 124 children in virologic failure in
2008 [21].
The effectiveness of this program is further demonstrated
by the significantly improved CD4%, hemoglobin levels, WAZ
scores, HAZ scores, and pVL levels observed in our cohort
once ART began. These data provide evidence that immune
reconstitution was occurring in these children and that they
were beginning to rebound from significantly impaired growth
and development common in HIV-positive children [31].
Similar to previous reports [32, 33], WAZ scores rebounded to
a greater degree and more quickly than HAZ scores, with
HAZ scores in older children not responding as well as in
Table 1.
Baseline Demographic Characteristics of Treatment-Naive Children at Time of Antiretroviral Therapy Initiation
Characteristic
Age (mo)
Median (IQR)
All (N = 1818)
Age ≤35 mo
(n = 302, 16.6%)
Age 36–59 mo
(n = 366, 20.1%)
Age ≥60 mo
(n = 1150, 63.3%)
74.5 (46.5–119.6)
24.4 (17.1–30.0)
48.6 (42.1–55.2)
105.9 (77.5–138.1)
1043 (57.4)
775 (42.6)
166 (55.0)
136 (45.0)
203 (55.5)
163 (44.5)
Sex
Male
Female
674 (58.6)
476 (41.4)
Infection route
Blood transfusion
Injecting drugs
Sexual contact
Mother-to-child
156 (9.0)
1 (0.1)
0
0
0
0
156 (14.4)
1 (0.1)
1 (0.1)
1584 (90.9)
0
298 (100.0)
0
358 (100.0)
1 (0.1)
928 (85.5)
769 (42.6)
1037 (57.4)
122 (40.5)
179 (59.5)
172 (47.3)
192 (52.7)
475 (41.6)
666 (58.4)
1306 (95.4)
63 (4.6)
202 (96.2)
8 (3.8)
260 (93.5)
18 (6.5)
844 (95.8)
37 (4.2)
1137 (93.1)
84 (6.9)
181 (93.8)
12 (6.2)
238 (96.7)
8 (3.3)
718 (91.8)
64 (8.2)
WHO clinical stage
I or II
III or IV
Hepatitis B serostatus
Negative
Positive
Hepatitis C serostatus
Negative
Positive
Weight-for-age z score
Median (IQR)
≥−1
≥−2, <−1
<−2
Height-for-age z score
Median (IQR)
−1.4 (−2.1, −0.8)
618 (34.1)
−1.5 (−2.5, −0.5)
101 (33.4)
−1.4 (−2.1, −0.5)
136 (37.3)
−1.4 (−2.1, −0.8)
381 (33.2)
671 (37.0)
89 (29.5)
123 (33.7)
459 (40.0)
525 (28.9)
112 (37.1)
106 (29.0)
307 (26.8)
−2.2 (−3.3, −1.1)
−2.2 (−3.3, −0.8)
−2.2 (−3.3, −1.3)
−2.2 (−3.3, −1.1)
≥−1
≥−2, <−1
416 (23.7)
397 (22.6)
84 (29.1)
57 (19.7)
77 (22.1)
84 (24.1)
255 (22.9)
256 (23.0)
<−2
940 (53.6)
148 (51.2)
188 (53.9)
604 (54.2)
8.8 (3.3–14.9)
12.1 (6.1–17.1)
CD4 cell percentage
Median (IQR)
9.2 (3.2–16.3)
7.7 (2.7–14.1)
≥15
386 (25.0)
90 (33.8)
93 (28.8)
203 (21.2)
≥10, <15
<10
310 (20.1)
849 (55.0)
71 (26.7)
105 (39.5)
60 (18.6)
170 (52.6)
179 (18.7)
574 (60.0)
Hemoglobin (g/L)
Median (IQR)
≥90
<90
111.0 (99.0–122.0)
1484 (86.2)
104.0 (89.0–114.0)
212 (73.9)
108.0 (95.0–120.0)
289 (82.3)
114.0 (103.0–124.0)
983 (90.7)
238 (13.8)
75 (26.1)
62 (17.7)
101 (9.3)
AZT/d4T regimen
AZT + 3TC + EFV/NVP
903 (59.3)
180 (73.5)
189 (61.6)
534 (54.9)
d4T + 3TC + EFV/NVP
621 (40.7)
65 (26.5)
118 (38.4)
438 (45.1)
EFV/NVP regimen
AZT/d4T + 3TC + EFV
384 (25.2)
20 (8.2)
93 (30.3)
271 (27.9)
AZT/d4T + 3TC + NVP
1140 (74.8)
225 (91.8)
214 (69.7)
701 (72.1)
Data are No. (%) unless otherwise specified.
Abbreviations: 3TC, lamivudine; AZT, zidovudine; d4T, stavudine; EFV, efavirenz; IQR, interquartile range; NVP, nevirapine; WHO, World Health Organization.
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740
•
Table 2. Deaths, Observed Time, Mortality, and Factors Associated With Death as Determined by Multivariate Cox Proportional Hazards Model Analysis
CID 2013:56 (1 March)
All Cases
Complete Cases Only
•
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Cases,
No.
Deaths,
No.
Observed
Time, CY
Mortality Rate per
100 CY (95% CI)
302
14
622
2.25 (1.23–3.78)
1.0
366
1150
12
67
875
2525
1.37 (.71–2.40)
2.65 (2.02–3.29)
.7 (.3–1.4)
1.2 (.7–2.2)
.28
.51
1043
775
55
38
2351
1672
2.34 (1.72–2.96)
2.27 (1.55–3.00)
1.0
1.0 (.6–1.4)
.81
156
1584
10
78
444
3343
2.25 (1.08–4.14)
2.29 (1.78–2.80)
1.0
.9 (.5–1.7)
.72
769
1037
17
74
1583
2414
1.07 (.63–1.72)
3.07 (2.37–3.76)
1.0
3.0 (1.8–5.1)
1306
63
56
4
3182
150
1.76 (1.30–2.22)
2.67 (.73–6.83)
1.0
1.5 (.5–4.2)
.42
1137
84
47
4
2739
252
1.72 (1.23–2.21)
1.59 (.43–4.06)
1.0
1.0 (.4–2.8)
.96
≥−1
≥−2, <−1
618
671
6
25
1406
1535
.43 (.16–.93)
1.63 (1.05–2.40)
1.0
3.8 (1.6–9.3)
<−2
525
62
1069
5.80 (4.35–7.24)
12.9 (5.6–29.7)
416
12
909
1.32 (.68–2.30)
1.0
281
.65 (.18–1.65)
397
15
907
1.65 (.93–2.73)
1.3 (0.6–2.7)
.53
282
1.19 (.51–2.34)
1.0 (.3–3.6)
.96
940
63
2023
3.11 (2.34–3.88)
2.4 (1.3–4.4)
<.01
665
2.83 (1.98–3.69)
1.1 (.4–3.5)
.84
≥15
386
6
762
.79 (.29–1.71)
302
.82 (.27–1.92)
≥10, <15
<10
310
849
3
56
723
1938
.41 (.09–1.21)
2.89 (2.13–3.65)
.6 (.1–2.3)
4.0 (1.7–9.4)
.44
<.01
251
675
.51 (.11–1.50)
2.90 (2.06–3.74)
.6 (.1–2.4)
2.4 (.9–6.0)
.46
.07
1484
238
54
30
3377
494
1.60 (1.17–2.03)
6.07 (4.10–8.67)
1.0
3.7 (2.4–5.8)
<.01
1067
161
1.48 (1.00–1.97)
5.23 (3.10–8.27)
1.0
2.2 (1.2–3.9)
.01
Characteristic
Unadjusted HR
(95% CI)
Cases,
No.
Mortality Rate per
100 CY (95% CI)
Adjusted HR
(95% CI)
511
717
.75 (.32–1.47)
2.70 (1.92–3.49)
1.0
2.4 (1.1–5.2)
<.01
398
477
.34 (.07–.98)
1.26 (.69–2.11)
1.0
3.1 (.8–11.6)
<.01
353
4.82 (3.27–6.37)
9.1 (2.5–33.2)
P Value
P Value
Age (mo)
≤35
36–59
≥60
Sex
Male
Female
Infection route
Blood transfusion
Mother-to-child
WHO clinical stage
I or II
III or IV
<.01
.02
Hepatitis B serostatus
Negative
Positive
Hepatitis C serostatus
Negative
Positive
Weight-for-age z score
Height-for-age z score
≥−1
≥−2, <−1
<−2
CD4 cell percentage (%)
1.0
.09
<.01
1.0
1.0
Hemoglobin (g/L)
≥90
<90
…
…
1228
.30
…
1.4 (0.8–2.4)
…
2.31 (1.75–2.78)
4022
1.0
1818
Overall
93
2.33 (1.76–2.89)
2.10 (1.15–3.52)
667
2792
65
AZT/d4T + 3TC + NVP
14
384
1140
EFV/NVP regimen
AZT/d4T + 3TC + EFV
1.6 (1.0–2.4)
Abbreviations: 3TC, lamivudine; AZT, zidovudine; CI, confidence interval; CY, child-years; d4T, stavudine; EFV, efavirenz; HR, hazard ratio; NVP, nevirapine; WHO, World Health Organization.
…
1.3 (.7–2.3)
2.63 (1.78–3.76)
1.47 (.94–2.18)
769
1.93 (1.31–2.56)
2.72 (1.90–3.54)
1545
1914
621
d4T + 3TC + EFV/NVP
37
903
AZT/d4T regimen
AZT + 3TC + EFV/NVP
42
1.0
.05
459
1.0
.35
P Value
Adjusted HR
(95% CI)
Mortality Rate per
100 CY (95% CI)
Characteristic
Cases,
No.
Deaths,
No.
Observed
Time, CY
Mortality Rate per
100 CY (95% CI)
Unadjusted HR
(95% CI)
P Value
Cases,
No.
Complete Cases Only
All Cases
Table 2 continued.
younger children. The immunologic and growth responses of
our cohort were similar or better than have been reported in
sub-Saharan Africa [27] and in other countries in Asia [12]. In
terms of pVL, it is clear that the ART medicines the children
in our cohort received were capable of suppressing viral load
in the majority of cases. Although we could not observe
changes in pVL over time or even at a single time point in
every child, we were able to examine pVL test results from the
majority of children in the cohort. Among these, 82% had
achieved viral suppression, somewhat better than the 70%
pooled proportion reported in a recent systematic review of
children on ART 12 months in developing countries [27].
Despite the fact that >90% of the children in our cohort
were infected via mother-to-child transmission, the median
age at treatment initiation was 6.2 years. Not surprisingly,
these children were seriously immunosuppressed as a consequence of their delayed treatment [5, 9, 28, 32, 34]. With significant mortality occurring in the first year of life without
treatment [35, 36]. it is likely that a majority of the children
infected with HIV at birth had already died by the age of
6. There are 2 major barriers to the early diagnosis of children
in China. First, there is a lack of widespread early infant diagnostic capability for infants born to HIV-positive mothers.
Second, a large proportion of those estimated to be HIVpositive have not yet been identified. China’s national HIV/
AIDS program is currently making a strong push to diagnose
and treat people earlier to reduce mortality [18, 37].
Our findings related to risk factors associated with mortality, including WAZ score <−2, WHO stage III or IV disease,
and hemoglobin level <90 g/L, were not unexpected. Severe
immunosuppression and low WAZ scores at time of treatment
initiation have consistently been identified in the literature as
risk factors for death in HIV-positive children [3, 5, 10, 15]. It
was somewhat surprising that we did not find a statistically
significant association between CD4% and mortality. Although it is not clear why this is the case, we speculate that it
may be related to the fact that approximately 15% of the children in our cohort did not have baseline CD4% data.
The primary strengths of our study were the large cohort
size, long follow-up time, and very limited loss to follow-up,
with only 5.4% of patients lost at 3 years. Retention in care is
a significant problem for ART programs around the world
[10, 29, 38, 39]. The major reasons for this high retention rate
are China’s household registration system and the strict management system in place for tracking patients on ART. Both of
these systems facilitate tracking and follow-up of patients by
public health personnel as well as capturing deaths. This is
especially true for children, who generally stay at their registered address to be cared for by relatives even if one or both
parents become migrant workers. Unfortunately, retention of
HIV-positive patients who have not yet engaged in the ART
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Figure 2. Mortality and survival rates at time intervals up to 36 months after antiretroviral therapy initiation. Abbreviation: ART, antiretroviral therapy.
Figure 3. Graphical representation of clinical outcomes of all children and specific age groups at time intervals up to 36 months after ART initiation.
A, Proportion of patients with CD4+ T-cell percentage ≥25%. B, Hemoglobin levels. C, Weight-for-age z scores. D, height-for-age z scores. Abbreviations: ART, antiretroviral therapy; CD4%, CD4+ T-cell percentage; HAZ, height-for-age z score; WAZ, weight-for-age z score.
742
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assistance with data checking of the manuscript preparation. The authors
also thank all pediatric antiretroviral treatment center and provincial CDC
staff members and all international partners at the Clinton Foundation
HIV/AIDS Initiative and the China offices of the United Nations Children’s Fund, the US Centers for Disease Control and Prevention Global
AIDS Program, and the World Health Organization.
Financial support. This work was supported by the Chinese government; the Important National Science and Technology Specific Projects
(2008ZX10001-007); and the Fogarty International Center and the National Institute on Drug Abuse of the US National Institutes of Health
(5U2RTW006918-07 to Y. Z.).
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
Figure 4. Graphical representation of proportions of patients who
achieved viral suppression (defined as viral loads <400 copies/mL) among
1149 children of the total 1818 children in the cohort (63%) who received
plasma viral load testing in 2010. Abbreviations: ART, antiretroviral
therapy; pVL, plasma viral load.
program is currently much less effective and is known to be
an area in urgent need of improvement [29].
There are limitations to this analysis. First, data were obtained from an observational cohort database and thus may
contain biases of which we are not aware. Second, our study
does have survivor selection bias associated with enrolling
median 6-year-old children, the majority of whom were infected at birth. Because without treatment approximately 50% of
vertically infected children die by the age of 2, and 75% by age
5 [36], many are neither diagnosed, nor treated in time. The
mortality rate in this analysis is therefore not generalizable to
all HIV-positive children in China. Third, our cohort only included children who initiated ART. Inclusion of HIV-positive
children who have not yet initiated ART would result in a
more complete assessment of China’s HIV/AIDS program and
should be the subject of future research [29]. Fourth, CD4%
and pVL testing have not always been available at all clinics,
resulting in missing values for some children, and ART eligibility guidelines have changed over time, resulting in some
children being eligible earlier than others. These issues may
have introduced biases that are difficult to quantify.
Results of the present study suggest that China’s pediatric
ART program effectively improves patient outcomes. The
lessons learned included herein can benefit other resourcelimited countries in their attempts to start or scale up similar
programs. As China’s program continues to expand and
improve, earlier diagnosis and treatment of infants and children should be made a major priority.
Notes
Acknowledgments. The authors thank Mingjie Zhang of the National
Center for AIDS/STD Control and Prevention, Chinese CDC, for
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